Nonlinear system tissue

As mentioned in Chapter 4, experiments have determined that the distribution of ASOs into tissues is nonlinear. This revelation invalidates the above BAV equation in that it is dependent on linear pharmacokinetics and the principle of superposition. A way to circumvent this problem is to decrease the drag input function (i.e., systemic presentation of the ASO) such that ASO plasma concentrations are maintained below the level at which saturation, and thus nonlinearity of the distribution processes, occurs. Drug administration by SC rather than IV administration has a reduced drug input rate and can produce such a scenario. The corresponding plasma-derived data are then suitable for the determination of absolute bioavailability - consistent with linear pharmacokinetic principles and the following equation ... 

In summary of the discussion above, systemic analyses are needed to detect patterns across multiple scales in both the spatial (e.g., molecules to cells to tissues) and temporal (e.g., nanoseconds to hours to years) dimensions. Based on such understanding, systems and dynamical medicine can be developed with the emphasis on the whole systems that change over time to address the nonlinearity and interconnectivity toward a holistic and proactive care. Here, the word systems underscores the concept of holism, and the term of dynamical medicine highlights the variations with the interwoven and integration of the spatial and temporal scopes see Fig. 2). 

A comprehensive overview of frequency-domain DOT techniques is given in [88]. Particular instraments are described in [166, 347, 410]. It is commonly believed that modulation techniques are less expensive and achieve shorter acquisition times, whereas TCSPC delivers a better absolute accuracy of optical tissue properties. It must be doubted that this general statement is correct for any particular instrument. Certainly, relatively inexpensive frequency-domain instruments can be built by using sine-wave-modulated LEDs, standard avalanche photodiodes, and radio or cellphone receiver chips. Instruments of this type usually have a considerable amplitude-phase crosstalk". Amplitude-phase crosstalk is a dependence of the measured phase on the amplitude of the signal. It results from nonlinearity in the detectors, amplifiers, and mixers, and from synchronous signal pickup [6]. This makes it difficult to obtain absolute optical tissue properties. A carefully designed system [382] reached a systematic phase error of 0.5° at 100 MHz. A system that compensates the amplitude-phase crosstalk via a reference channel reached an RMS phase error of 0.2° at 100 MHz [370]. These phase errors correspond to a time shift of 14 ps and 5.5 ps RMS, respectively. 

In tissue, sinusoidal current waveform generates potential differences that are also sinusoidal if the system is linear. Is the current amplitude for onset of nonlinearity dependent on the sine frequency ... 

Electrolytic effects are related to DC, applied or rectified by nonlinear effects at the electrodes or in the tissue. Also with very low-frequency AC (e.g., <10 Hz), each half period may last so long as to cause considerable nonreversible electrolytic effects. With large quantities of electricity (Q = It) passed, the electrolytic effects may be systemic and dangerous (lightning and high-voltage accidents). The risk of skin chemical bums is greater under the cathode (alkali formation) than the anode (acid formation), the natural skin pH is on the acidic side (pH < 5.5). 

Blood and lymphatic vessels are soft tissues with densities which exhibit nonlinear stress-strain relationships [1]. The walls of blood and lymphatic vessels show not only elastic [2, 3] or pseudoelastic [4] behavior, but also possess distinctive inelastic character [5, 6] as well, including viscosity, creep, stress relaxation and pressure-diameter hysteresis. The mechanical properties of these vessels depend largely on the constituents of their walls, especially the collagen, elastin, and vascular smooth muscle content. In general, the walls of blood and lymphatic vessels are anisotropic. Moreover, their properties are affected by age and disease state. This section presents the data concerning the characteristic dimensions of arterial tree and venous system the constituents and mechanical properties of the vessel walls. Water permeability or hydraulic conductivity of blood vessel walls have been also included, because this transport property of blood vessel wall is believed to be important both in nourishing the vessel walls and in affecting development of atherosclerosis [7-9]. 

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